Crystalline forms of a factor xa inhibitor

ABSTRACT

The instant invention provides crystalline forms of 3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one and its solvates thereof, processes for the production of such crystalline forms; pharmaceutical compositions comprising such crystalline forms; and methods of treating thromboembolic disorders with such crystalline forms or such pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of application Ser. No.11/302,692, filed Dec. 14, 2005, which claims the priority benefit ofU.S. Provisional Application No. 60/636,387, filed Dec. 15, 2004 and thepriority benefit of U.S. Provisional Application No. 60/737,985, filedNov. 18, 2005, all of which are expressly incorporated fully herein byreference.

FIELD OF THE INVENTION

The present invention relates to crystalline forms of3-(1-hydroxy-1-methyl-ethyl)- 1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-oneand its solvates thereof, processes for the production thereof,pharmaceutical compositions thereof, and methods of treatingthromboembolic disorders, therewith.

BACKGROUND OF THE INVENTION

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617-629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

U.S. Patent Application Publication No. 2003/0191115, which is hereinincorporated by reference, discloses3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one(hereinafter referred to as “Compound (I)”):

Compound (I) is a highly potent and selective inhibitor of coagulationFactor Xa and thus is useful in preventing or treating thromboembolicdisorders.

Treatment or prevention of the foregoing disorders may be accomplishedby administering a therapeutically effective amount of Compound (I) to ahuman or animal subject in need of such treatment or prevention. Thetreatment with Compound (I) may be accomplished by its use as a singlecompound, as a pharmaceutical composition ingredient, or in combinationwith other therapeutic agents. Compound (I) may be administered by oraladministration, continuous intravenous infusion, bolus intravenousadministration or any other suitable route such that it preferablyachieves the desired effect of preventing the Factor Xa inducedformation of thrombin from prothrombin.

Crystalline forms of Compound (I) have not been known to existpreviously. There exists a need for crystalline forms which may exhibitdesirable and beneficial chemical and physical properties. There alsoexists a need for reliable and reproducible methods for the manufacture,purification, and formulation of Compound (I) to permit its feasiblecommercialization. The present invention is directed to these, as wellas other important aspects.

SUMMARY OF THE INVENTION

The present invention provides crystalline forms of Compound (I):

processes for the production of such forms; pharmaceutical compositionscomprising such forms; and methods of treating thromboembolic disorderswith such crystalline forms, or such pharmaceutical compositions.Embodiments of these crystalline forms include those characterizedherein as Forms N-1, N-3, H2-2, DC-4 and EGDA. 5-5. The names usedherein to characterize a specific form, e.g. “N-1” etc., should not beconsidered limiting with respect to any other substance possessingsimilar or identical physical and chemical characteristics, but ratherit should be understood that these designations are mere identifiersthat should be interpreted according to the characterization informationalso presented herein.

These and other aspects of the invention will become more apparent fromthe following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated by reference to the accompanying drawingsdescribed below.

FIG. 1 shows calculated (22° C.) and observed (room temperature) powderX-ray diffraction patterns (CuKα λ=1.5418 Å) of Form N-1 of crystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 2 shows calculated (22° C.) and observed (room temperature) powderX-ray diffraction patterns (CuKα λ=1.5418 Å) of Form N-3 of crystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 3 shows calculated (−50° C.) and observed (−50° C.) powder X-raydiffraction patterns (CuKα λ=1.5418 Å) of Form N-3 of crystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 4 shows observed (room temperature) and calculated (roomtemperature and −50° C.) powdered X-ray diffraction patterns (CuKαλ=1.5418 Å) of Form H2-2 of crystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 5 shows calculated (22° C.) and observed (room temperature) powderX-ray diffraction patterns (CuKα λ=1.5418 Å) of Form DC-4 of crystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 6 shows calculated (−50° C.) and observed (−50° C.) powder X-raydiffraction patterns (CuKα λ=1.5418 Å) of Form DC-4 of crystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 7 shows differential scanning calorimetry thermogram of Form N-1 ofcrystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 8 shows differential scanning calorimetry thermogram of Form N-3 ofcrystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 9 shows differential scanning calorimetry thermogram of Form H2-2of crystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 10 shows differential scanning calorimetry thermogram of Form DC-4of crystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 11 shows thermogravimetric analysis curve of Form N-1 ofcrystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 12 shows thermogravimetric analysis curve of Form N-3 ofcrystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl9-1,4,5,6-tetrahydro-pyrazolo[3,4-c9 pyridin-7-one.

FIG. 13 shows thermogravimetric analysis curve of Form H2-2 ofcrystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 14 shows thermogravimetric analysis curve of Form DC-4 ofcrystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

FIG. 15 shows calculated (22° C.) and observed (room temperature) powderX-ray diffraction patterns (CuKα μ=1.5418 Å) of Form EGDA. 5-5 ofcrystalline3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides, at least in part, crystalline forms ofCompound (I) as a novel material, in particular in pharmaceuticallyacceptable form. The term “pharmaceutically acceptable”, as used herein,refers to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable forcontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio. In certain preferredembodiments, Compound (I) is in substantially pure form. The term“substantially pure”, as used herein, means a compound having a puritygreater than about 90% including greater than 90, 91, 92, 93, 94, 95,96, 97, 98, and 99 weight %, and also including equal to about 100weight % of Compound (I), based on the weight of the compound. Theremaining material comprises other form(s) of the compound, and/orreaction impurities and/or processing impurities arising from itspreparation. For example, a crystalline form of Compound (I) may bedeemed substantially pure in that it has a purity greater than 90 weight%, as measured by means that are at this time known and generallyaccepted in the art, where the remaining less than 10 weight % ofmaterial comprises other form(s) of Compound (I) and/or reactionimpurities and/or processing impurities.

As used herein “polymorph” refers to crystalline forms having the samechemical composition but different spatial arrangements of themolecules, and/or ions forming the crystal.

As used herein “solvate” refers to a crystalline form of a molecule,and/or ions that further comprises molecules of a solvent or solventsincorporated into the crystalline structure. The solvent molecules inthe solvate may be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. For example, asolvate with a nonstoichiometric amount of solvent molecules may resultfrom partial loss of solvent from the solvate.

As used herein “amorphous” refers to a solid form of a molecule, and/orions that is not crystalline. An amorphous solid does not display anX-ray diffraction pattern with sharp maxima.

Compound (I) may be prepared using methods well known to the skilledartisan of organic synthesis, as well as methods taught in commonlyassigned U.S. Application Publication No. 2003/0191115, and U.S.application Ser. Nos. 11/234,942, 11/235,647, and 11/235,731, thedisclosures of which are hereby incorporated herein by reference, intheir entireties.

Compound (I) is formed from Compound (II), under inert atmosphere,typically N₂, by contacting 2-hydroxy-pyridine, in the presence of CuI,potassium tert-butoxide and 1,10-phenanthroline in DMF. The reactionmixture is heated to 125° C. for 19-24 h. Once the end-point is reached,the reaction mixture is cooled to about 125° C., and solid potassiumphosphate powder is added. After 45 min of stirring, ammonium hydroxidesolution is added slowly and stirring is extended for 30 min while theproduct crystallizes out. The resulting slurry is then filtered andwashed successively with ammonium hydroxide, water, and MTBE. Theisolated final product is dried at 50-60° C. under vacuum.

Samples of the crystalline forms may be provided with substantially purephase homogeneity, indicating the presence of a dominant amount of asingle crystalline form and optionally minor amounts of one or moreother crystalline forms. The presence of more than one crystalline formin a sample may be determined by techniques such as powder X-raydiffraction (PXRD) or solid state nuclear magnetic resonancespectroscopy (SSNMR). For example, the presence of extra peaks in thecomparison of an experimentally measured PXRD pattern with a simulatedPXRD pattern may indicate more than one crystalline form in the sample.The simulated PXRD may be calculated from single crystal X-ray data. seeSmith, D. K., “A FORTRAN Program for Calculating X-Ray PowderDiffraction Patterns,” Lawrence Radiation Laboratory, Livermore, Calif.,UCRL-7196, April 1963. Preferably, the crystalline form hassubstantially pure phase homogeneity as indicated by less than 10%,preferably less than 5%, and more preferably less than 2% of the totalpeak area in the experimentally measured PXRD pattern arising from theextra peaks that are absent from the simulated XRPD pattern. Mostpreferred is a crystalline form having substantially pure phasehomogeneity with less than 1% of the total peak area in theexperimentally measured PXRD pattern arising from the extra peaks thatare absent from the simulated PXRD pattern.

Procedures for the preparation of crystalline forms are known in theart. The crystalline forms may be prepared by a variety of methods,including for example, crystallization or recrystallization from asuitable solvent, sublimation, growth from a melt, solid statetransformation from another phase, crystallization from a supercriticalfluid, and jet spraying. Techniques for crystallization orrecrystallization of crystalline forms from a solvent mixture include,for example, evaporation of the solvent, decreasing the temperature ofthe solvent mixture, crystal seeding a supersaturated solvent mixture ofthe molecule and/or salt, freeze drying the solvent mixture, andaddition of antisolvents (countersolvents) to the solvent mixture. Highthroughput crystallization techniques may be employed to preparecrystalline forms including polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, andcharacterization of drug crystals are discussed in Solid-State Chemistryof Drugs, S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell, 2^(nd) Edition,SSCI, West Lafayette, Ind., 1999.

For crystallization techniques that employ solvent, the choice ofsolvent or solvents is typically dependent upon one or more factors,such as solubility of the compound, crystallization technique, and vaporpressure of the solvent. Combinations of solvents may be employed, forexample, the compound may be solubilized into a first solvent to afforda solution, followed by the addition of an antisolvent to decrease thesolubility of the compound in the solution and to afford the formationof crystals. An antisolvent is a solvent in which the compound has lowsolubility. Suitable solvents for preparing crystals include polar andnonpolar solvents.

In one method to prepare crystals, Compound (I) is suspended and/orstirred in a suitable solvent to afford a slurry, which may be heated topromote dissolution. The term “slurry”, as used herein, means asaturated solution of Compound (I), which may also contain an additionalamount of Compound (I) to afford a heterogeneous mixture of Compound (I)and a solvent at a given temperature. Suitable solvents in this regardinclude, for example, polar aprotic solvents, and polar protic solvents,and nonpolar solvents, and mixtures of two or more of these.

Suitable polar aprotic solvents include, for example, dicholomethane(CH₂Cl₂ or DCM), tetrahydrofuran (THF), acetone, methyl ethyl ketone(MEK), dimethylformamide (DMF), dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile (ACN orMeCN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate, methylacetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IpOAc), butylacetate (BuOAc), t-butyl acetate, hexachloroacetone, dioxane, sulfolane,N,N-dimethylpropionamide, nitromethane, nitrobenzene andhexamethylphosphoramide.

Suitable polar protic solvents include, for example, alcohols andglycols, such as H₂O, methanol, ethanol, 1-propanol, 2-propanol,isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), i-butylalcohol, t-butyl alcohol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol,2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentylalcohol, t-pentyl alcohol, diethylene glycol monomethyl ether,diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol,glycerol and methyl t-butyl ether (MTBE).

Preferred solvents include, for example, acetone, H₂O, MeCN, CH₂Cl₂,THF, ethanol, n-BuOH, 2-BuOH, IPA, and EtOAc.

Other solvents suitable for the preparation of slurries of Compound (I),in addition to those exemplified above, would be apparent to one skilledin the art, based on the present disclosure.

Seed crystals may be added to any crystallization mixture to promotecrystallization. As will be clear to the skilled artisan, seeding isused as a means of controlling growth of a particular crystalline formor as a means of controlling the particle size distribution of thecrystalline product. Accordingly, calculation of the amount of seedsneeded depends on the size of the seed available and the desired size ofan average product particle as described, for example, in “Programmedcooling of batch crystallizers,” J. W. Mullin and J. Nyvlt, ChemicalEngineering Science, 1971, 26, 369-377. In general, seeds of small sizeare needed to effectively control the growth of crystals in the batch.Seeds of small size may be generated by sieving, milling, or micronizingof larger crystals, or by micro-crystallization of solutions. Careshould be taken that milling or micronizing of crystals does not resultin any change in crystallinity of the desired crystal form or formconversions (i.e. change to amorphous or to another polymorph).

A cooled mixture may be filtered under vacuum, and the isolated solidsmay be washed with a suitable solvent, such as cold recrystallizationsolvent, and dried under a nitrogen purge to afford the desiredcrystalline form. The isolated solids may be analyzed by a suitablespectroscopic or analytical technique, such as SSNMR, DSC, PXRD, or thelike, to assure formation of the preferred crystalline form of theproduct. The resulting crystalline form is typically produced in anamount of greater than about 70 weight % isolated yield, but preferablygreater than 90 weight % based on the weight of Compound (I) originallyemployed in the crystallization procedure. The product may be comilledor passed through a mesh screen to delump the product, if necessary.

Crystalline forms may be prepared directly from the reaction medium ofthe final process step for preparing Compound (I). This may be achieved,for example, by employing in the final process step a solvent or mixtureof solvents from which Compound (I) may be crystallized. Alternatively,crystalline forms may be obtained by distillation or solvent additiontechniques. Suitable solvents for this purpose include any of thosesolvents described herein, including protic polar solvents such asalcohols, and aprotic polar solvents such as ketones.

By way of general guidance, the reaction mixture may be filtered toremove any undesired impurities, inorganic salts, and the like, followedby washing with reaction or crystallization solvent. The resultingsolution may be concentrated to remove excess solvent or gaseousconstituents. If distillation is employed, the ultimate amount ofdistillate collected may vary, depending on process factors including,for example, vessel size, stirring capability, and the like, by way ofgeneral guidance, the reaction solution may be distilled to about 1/10the original volume before solvent replacement is carried out. Thereaction may be sampled and assayed to determine the extent of thereaction and the wt % product in accordance with standard processtechniques. If desired, additional reaction solvent may be added orremoved to optimize reaction concentration. Preferably, the finalconcentration is adjusted to about 50 wt % at which point a slurrytypically results.

It may be preferable to add solvents directly to the reaction vesselwithout distilling the reaction mixture. Preferred solvents for thispurpose are those which may ultimately participate in the crystallinelattice as discussed above in connection with solvent exchange. Althoughthe final concentration may vary depending on desired purity, recoveryand the like, the final concentration of Compound (I) in solution ispreferably about 4% to about 7%. The reaction mixture may be stirredfollowing solvent addition and simultaneously warmed. By way ofillustration, the reaction mixture may be stirred for about 1 hour whilewarming to about 70° C. The reaction is preferably filtered hot andwashed with either the reaction solvent, the solvent added or acombination thereof. Seed crystals may be added to any crystallizationsolution to initiate crystallization.

The various forms described herein may be distinguishable from oneanother through the use of various analytical techniques known to one ofordinary skill in the art. Such techniques include, but are not limitedto, solid state nuclear magnetic resonance (SSNMR) spectroscopy, X-raypowder diffraction (PXRD), differential scanning calorimetry (DSC),and/or thermogravimetric analysis (TGA).

One of ordinary skill in the art will appreciate that an X-raydiffraction pattern may be obtained with a measurement error that isdependent upon the measurement conditions employed. In particular, it isgenerally known that intensities in a X-ray diffraction pattern mayfluctuate depending upon measurement conditions employed. It should befurther understood that relative intensities may also vary dependingupon experimental conditions and, accordingly, the exact order ofintensity should not be taken into account. Additionally, a measurementerror of diffraction angle for a conventional X-ray diffraction patternis typically about 5% or less, and such degree of measurement errorshould be taken into account as pertaining to the aforementioneddiffraction angles. Consequently, it is to be understood that thecrystal forms of the instant invention are not limited to the crystalforms that provide X-ray diffraction patterns completely identical tothe X-ray diffraction patterns depicted in the accompanying Figuresdisclosed herein. Any crystal forms that provide X-ray diffractionpatterns substantially identical to those disclosed in the accompanyingFigures fall within the scope of the present invention. The ability toascertain substantial identities of X-ray diffraction patterns is withinthe purview of one of ordinary skill in the art.

In one aspect of the present invention, Form N-1 of Compound (I) may becharacterized by unit cell parameters substantially equal to thefollowing:

Cell dimensions: a = 9.534(1) Å b = 9.842(1) Å c = 13.469(1) Å α =87.95(1) β = 83.18(1) γ = 70.22(1) Space group P-1 Molecules/asymmetricunit 1 wherein the crystalline form is at about +22° C.

In a different aspect, Form N-1 may be characterized by fractionalatomic coordinates substantially as listed in Table 3.

In a different aspect, Form N-1 may be characterized by a powder X-raydiffraction pattern (FIG. 1) comprising the following 2θ values (CuKαλ=1.5418 Å): 6.6±0.1, 11.3±0.1, 12.5±0.1, 15.6±0.1, 19.2±0.1, and20.3±0.1, at about 22° C.

In a different aspect, Form N-1 may be characterized by a differentialscanning calorimetry thermogram (FIG. 7) having a peak onset at about222-226° C.

In a different aspect, Form N-1 may be characterized by a thermalgravimetric analysis curve (FIG. 11) having a negligible weight loss upto about 200° C.

In another aspect, Form N-3 of Compound (I) may be characterized by unitcell parameters substantially equal to the following:

Cell dimensions: a = 8.959(3) Å b = 9.840(2) Å c = 14.826(6) Å α =76.27(2) β = 86.38(2) γ = 69.18(2) Space group P-1 Molecules/asymmetricunit 1 wherein the crystalline form is at about +22° C.

In a different aspect, Form N-3 of Compound (I) may be characterized byunit cell parameters substantially equal to the following:

Cell dimensions: a = 8.933(1) Å b = 9.811(3) Å c = 14.751(5) Å α =76.32(2) β = 85.99(2) γ = 69.01(2) Space group P-1 Molecules/asymmetricunit 1 wherein the crystalline form is at −50° C.

In a different aspect, Form N-3 may be characterized by fractionalatomic coordinates substantially as listed in Table 4.

In a different aspect, Form N-3 may be characterized by fractionalatomic coordinates substantially as listed in Table 4a.

In a different aspect, Form N-3 may be characterized by a powder X-raydiffraction pattern (FIG. 2) comprising the following 2θ values (CuKαλ=1.5418 Å): 6.1±0.1, 9.9±0.1, 12.2±0.1, 15.4±0.1, 19.3±0.1, 23.1±0.1and 24.4±0.1, at about 22° C.

In a different aspect, Form N-3 may be characterized by a differentialscanning calorimetry thermogram (FIG. 8) having a peak onset at about183-187° C.

In a different aspect, Form N-3 may be characterized by a thermalgravimetric analysis curve (FIG. 12) having a negligible weight loss upto about 150° C.

In another aspect, Form H2-2 of Compound (I) may be characterized byunit cell parameters substantially equal to the following:

Cell dimensions: a = 16.445(2) Å b = 17.319(1) Å c = 18.997(2) Å α =71.65(1) (1) β = 78.86(1) γ = 87.78(1) Space group P-1Molecules/asymmetric unit 4 wherein the crystalline form is at about−50° C.

In a different aspect, Form H2-2 may be characterized by fractionalatomic coordinates substantially as listed in Table 5.

In a different aspect, Form H2-2 may be characterized by a powder X-raydiffraction pattern (FIG. 4) comprising the following 2θ values (CuKαλ=1.5418 Å): 5.4±0.1, 9.7±0.1, 12.2±0.1, 14.6±0.1, 16.2±0.1 and22.3±0.1, at about 22° C.

In a different aspect, Form H2-2 may be characterized by a differentialscanning calorimetry thermogram (FIG. 9) having a an endotherm in therange about room temperature to 80° C.

In a different aspect, Form H2-2 may be characterized by a thermalgravimetric analysis curve (FIG. 13) having a weight loss of about 7.1%up to about 80° C.

In another aspect, Form DC-4 of Compound (I) may be characterized byunit cell parameters substantially equal to the following:

Cell dimensions: a = 8.951(2) Å b = 9.789(3) Å c = 17.263(4) Å α =69.30(2) β = 83.24(2) γ = 69.78(2) Space group P-1 Molecules/asymmetricunit 1 wherein the crystalline form is at about +22° C.

In a different aspect, Form DC-4 of Compound (I) may be characterized byunit cell parameters substantially equal to the following:

Cell dimensions: a = 8.933(1) Å b = 9.778(1) Å c = 17.227(1) Å α =69.19(1) β = 83.06(1) γ = 69.66(1) Space group P-1 Molecules/asymmetricunit 1 wherein the crystalline form is at about −50° C.

In a different aspect, Form DC-4 may be characterized by fractionalatomic coordinates substantially as listed in Table 6.

In a different aspect, Form DC-4 may be characterized by fractionalatomic coordinates substantially as listed in Table 6a.

In a different aspect, Form DC-4 may be characterized by a powder X-raydiffraction pattern (FIG. 5) comprising the following 2θ values (CuKαλ=1.5418 Å): 5.5±0.1, 11.8±0.1, 13.8±0.1, 15.2±0.1, 18.8±0.1, 21.1±0.1and 23.8±0.1, at about 22° C.

In a different aspect, Form DC-4 may be characterized by a differentialscanning calorimetry thermogram (FIG. 10) having an endotherm in therange about 65-85° C.

In a different aspect, Form DC-4 may be characterized by a thermalgravimetric analysis curve (FIG. 14) having a weight loss of about 15.2%up to about 85° C.

In one aspect of the present invention, Form EGDA. 5-5 of Compound (I)may be characterized by unit cell parameters substantially equal to thefollowing:

Cell dimensions: a = 9.005(3) Å b = 9.854(2) Å c = 16.283(5) Å α =84.88(2) β = 81.95(2) γ = 68.19(1) Space group P-1 Molecules/asymmetricunit 1 wherein the crystalline form is at about +22° C.

In a different aspect, Form N-1 may be characterized by fractionalatomic coordinates substantially as listed in Table 7.

In a different aspect, Form EGDA. 5-5 may be characterized by a powderX-ray diffraction pattern (FIG. 15) comprising the following 2θ values(CuKα λ=1.5418 Å): 5.5±0.1, 12.0±0.1, 12.5±0.1, 14.8±0.1, 16.8±0.1,20.6±0.1, 21.5±0.1, 22.7±0.1, 24.4±0.1, at about 22° C.

Although Form N-1 is the thermodynamically more stable form at roomtemperature, different forms have been found to co-crystallize fromseveral different solvent mixtures. As Form N-3 melts ˜40° C. lower thanForm N-1, these forms are effectively monotropic-with Form N-1 morestable at all temperatures. Moisture sorption isotherms of Form N-1suggest that Form N-1 is essentially non-hygroscopic.

The crystalline forms of Compound (I) described herein may be formulatedinto pharmaceutical compositions and/or employed in therapeutic and/orprophylactic methods. These methods include, but are not limited to, theadministration of the crystalline compound (I), alone or in combinationwith one or more other pharmaceutically active agents, including agentsthat may be useful in the treatment of the disorders mentioned herein.

“Therapeutically effective amount” is intended to include an amount ofthe crystalline forms of Compound (I) that is effective whenadministered alone or in combination to inhibit factor Xa. If Compound(I) is used in combination with another medication, the combination ofcompounds described herein may result in a synergistic combination.Synergy, as described for example by Chou and Talalay, Adv. EnzymeRegul. 1984, 22, 27-55, occurs when the effect of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased antithrombotic effect, or some other beneficialeffect of the combination compared with the individual components.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

The crystalline forms of Compound (I) and pharmaceutical compositionsthereof may be useful in inhibiting Factor Xa. Accordingly, the presentinvention provides methods for the treatment and/or prevention ofthromboembolic disorders in mammals (i.e., factor Xa-associateddisorders). In general, a thromboembolic disorder is a circulatorydisease caused by blood clots (i.e., diseases involving fibrinformation, platelet activation, and/or platelet aggregation). The term“thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, and thromboembolic disorders in the chambersof the heart. The term “thromboembolic disorders” as used herein alsoincludes specific disorders selected from, but not limited to, unstableangina or other acute coronary syndromes, atrial fibrillation, first orrecurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from (a) prosthetic valves or other implants, (b)indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e)hemodialysis, or (f) other procedures in which blood is exposed to anartificial surface that promotes thrombosis. It is noted that thrombosisincludes occlusion (e.g. after a bypass) and reocclusion (e.g., duringor after percutaneous transluminal coronary angioplasty). Thethromboembolic disorders may result from conditions including but notlimited to atherosclerosis, surgery or surgical complications, prolongedimmobilization, arterial fibrillation, congenital thrombophilia, cancer,diabetes, effects of medications or hormones, and complications ofpregnancy. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa or thrombin.

The methods preferably comprise administering to a patient apharmaceutically effective amount of the novel crystals of the presentinvention, preferably in combination with one or more pharmaceuticallyacceptable carriers and/or excipients. The relative proportions ofactive ingredient and carrier and/or excipient may be determined, forexample, by the solubility and chemical nature of the materials, chosenroute of administration and standard pharmaceutical practice.

The crystalline forms of Compound (I) may be administered to a patientin such oral dosage forms as tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixirs, tinctures, suspensions, syrups, and emulsions. Theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.They may be administered alone, but generally will be administered witha pharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the crystalline forms of Compound (I) will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder. Obviously, several unitdosage forms may be administered at about the same time. The dosage ofthe crystalline form of Compound (I) that will be most suitable forprophylaxis or treatment may vary with the form of administration, theparticular crystalline form of the compound chosen and the physiologicalcharacteristics of the particular patient under treatment. Broadly,small dosages may be used initially and, if necessary, increased bysmall increments until the desired effect under the circumstances isreached.

By way of general guidance, in the adult, suitable doses may range fromabout 0.001 to about 1000 mg/Kg body weight, and all combinations andsubcombinations of ranges and specific doses therein. Preferred dosesmay be from about 0.01 to about 100 mg/kg body weight per day byinhalation, preferably 0.1 to 70, more preferably 0.5 to 20 mg/Kg bodyweight per day by oral administration, and from about 0.01 to about 50,preferably 0.01 to 10 mg/Kg body weight per day by intravenousadministration. In each particular case, the doses may be determined inaccordance with the factors distinctive to the subject to be treated,such as age, weight, general state of health and other characteristicswhich can influence the efficacy of the medicinal product. Thecrystalline forms of Compound (I) may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily.

For oral administration in solid form such as a tablet or capsule, thecrystalline forms of Compound (I) can be combined with a non-toxic,pharmaceutically acceptable inert carrier, such as lactose, starch,sucrose, glucose, methylcellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, mannitol, sorbitol and the like.

Preferably, in addition to the active ingredient, solid dosage forms maycontain a number of additional ingredients referred to herein as“excipients”. These excipients include among others diluents, binders,lubricants, glidants and disintegrants. Coloring agents may also beincorporated. “Diluents”, as used herein, are agents which impart bulkto the formulation to make a tablet a practical size for compression.Examples of diluents are lactose and cellulose. “Binders”, as usedherein, are agents used to impart cohesive qualities to the poweredmaterial to help ensure the tablet will remain intact after compression,as well as improving the free-flowing qualities of the powder. Examplesof typical binders are lactose, starch and various sugars. “Lubricants”,as used herein, have several functions including preventing the adhesionof the tablets to the compression equipment and improving the flow ofthe granulation prior to compression or encapsulation. Lubricants are inmost cases hydrophobic materials. Excessive use of lubricants isundesired, however, as it may result in a formulation with reduceddisintegration and/or delayed dissolution of the drug substance.“Glidants”, as used herein, refer to substances which may improve theflow characteristics of the granulation material. Examples of glidantsinclude talc and colloidal silicon dioxide. “Disintegrants”, as usedherein, are substances or a mixture of substances added to a formulationto facilitate the breakup or disintegration of the solid dosage formafter administration. Materials that may serve as disintegrants includestarches, clays, celluloses, algins, gums and cross-linked polymers. Agroup of disintegrants referred to as “super-disintegrants” generallyare used at a low level in the solid dosage form, typically 1% to 10% byweight relative to the total weight of the dosage unit. Croscarmelose,crospovidone and sodium starch glycolate represent examples of across-linked cellulose, a cross-linked polymer and a cross-linkedstarch, respectively. Sodium starch glycolate swells seven-totwelve-fold in less than 30 seconds effectively disintegrating thegranulations that contain it.

The disintegrant preferably used in the present invention is selectedfrom the group comprising modified starches, croscarmallose sodium,carboxymethylcellulose calcium and crospovidone. A more preferreddisintegrant in the present invention is a modified starch such assodium starch glycolate.

Preferred carriers include capsules or compressed tablets which containthe solid pharmaceutical dosage forms described herein. Preferredcapsule or compressed tablet forms generally comprise a therapeuticallyeffective amount of the crystalline forms of Compound (I) and one ormore disintegrants in an amount greater than about 10% by weightrelative to the total weight of the contents of the capsule or the totalweight of the tablet.

Preferred capsule formulations may contain the crystalline forms ofCompound (I) in an amount from about 5 to about 1000 mg per capsule.Preferred compressed tablet formulations contain the crystalline formsof Compound (I) in an amount from about 5 mg to about 800 mg per tablet.More preferred formulations contain about 50 to about 200 mg per capsuleor compressed tablet. Preferably, the capsule or compressed tabletpharmaceutical dosage form comprises a therapeutically effective amountof Form N-1 of Compound (I); a surfactant; a disintegrant; a binder; alubricant; and optionally additional pharmaceutically acceptableexcipients such as diluents, glidants and the like; wherein thedisintegrant is selected from modified starches; croscarmallose sodium,carboxymethylcellulose calcium and crospovidone.

For oral administration in liquid form, the crystalline forms ofCompound (I) can be combined with any oral, non-toxic pharmaceuticallyacceptable inert carrier such as ethanol, glycerol, water and the like.The liquid composition may contain a sweetening agent which to make thecompositions more palatable. The sweetening agent can be selected from asugar such as sucrose, mannitol, sorbitol, xylitol, lactose, etc. or asugar substitute such as cyclamate, saccaharin, aspartame, etc. If sugarsubstitutes are selected as the sweetening agent the amount employed inthe compositions of the invention will be substantially less than ifsugars are employed. Taking this into account, the amount of sweeteningagent may range from about 0.1 to about 50% by weight, and allcombinations and subcombinations of ranges and specific amounts therein.Preferred amounts range from about 0.5 to about 30% by weight.

The more preferred sweetening agents are the sugars and particularlysucrose. The particle size of the powdered sucrose used has been foundto have a significant influence in the physical appearance of thefinished composition and its ultimate acceptance for taste. Thepreferred particle size of the sucrose component when used is in therange of from 200 to less than 325 mesh US Standard Screen, and allcombinations and subcombinations of ranges and specific particle sizestherein.

Sterile injectable solutions may be prepared by incorporating thecrystalline forms of Compound (I) in the required amounts, in theappropriate solvent, with various of the other ingredients enumeratedherein, as required, followed by filtered sterilization. Generally,dispersions may be prepared by incorporating the sterilized activeingredient into a sterile vehicle which contains the dispersion mediumand any other required ingredients. In the case of sterile powders forthe preparation of sterile injectable solutions, the preferred methodsof preparation may include vacuum drying and the freeze drying techniquewhich may yield a powder of the active ingredient, plus any additionaldesired ingredient from the previously sterile-filtered solutionthereof.

As would be apparent to a person of ordinary skill in the art, oncearmed with the teachings of the present disclosure, when dissolved,Compound (I) loses its crystalline structure, and is thereforeconsidered to be a solution of Compound (I). All forms of the presentinvention, however, may be used for the preparation of liquidformulations in which Compound (I) may be, for example, dissolved orsuspended. In addition, the crystalline forms of Compound (I) may beincorporated into solid formulations.

The liquid compositions may also contain other components routinelyutilized in formulating pharmaceutical compositions. One example of suchcomponents is lecithin. Its use in compositions of the invention as anemulsifying agent in the range of from 0.05 to 1% by weight, and allcombinations and subcombinations of ranges and specific amounts therein.More preferably, emulsifying agents may be employed in an amount of fromabout 0.1 to about 0.5% by weight. Other examples of components that maybe used are antimicrobial preservatives, such as benzoic acid orparabens; suspending agents, such as colloidal silicon dioxide;antioxidants; topical oral anesthetics; flavoring agents; and colorants.

The selection of such optional components and their level of use in thecompositions of the invention is within the level of skill in the artand will be even better appreciated from the working examples providedhereinafter.

The crystalline forms of Compound (I) may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidine pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol or polyethylene oxide-polylysinesubstituted with palmitolyl residues. Furthermore, the crystallineCompound (I) may be coupled to a class of biodegradable polymers usefulin achieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked oramphipathic block copolymers of hydrogels.

Gelatin capsules of the crystalline forms of Compound (I) may containthe crystalline Compound (I) and the liquid or solid compositionsdescribed herein. Gelatin capsules may also contain powdered carrierssuch as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Tablets can be sugar coated or filmcoated to mask any unpleasant taste and to protect the tablet from theatmosphere or enteric coated for selective disintegration in thegastrointestinal track.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols, such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral solutions are prepared by dissolving thecrystalline Compound (I) in the carrier and, if necessary, addingbuffering substances. Anti-oxidizing agents such as sodium bisulfite,sodium sulfite, or ascorbic acid either alone or combined, are suitablestabilizing agents. Citric acid and its salts and sodium EDTA may alsobe employed. Parenteral solutions may also contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Co., the disclosures of whichare hereby incorporated herein by reference, in their entireties. Usefulpharmaceutical dosage- forms for administration of the compounds of thisinvention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 mg of powdered activeingredient (i.e., Factor Xa inhibitor), 150 mg of lactose, 50 mg ofcellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil can be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 mg of the active ingredient. The capsules should then bewashed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatingsmay be applied to increase palatability or delay absorption.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 25 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is sterilized bycommonly used techniques.

Nasal Spray

An aqueous solution is prepared such that each 1 mL contains 10 mg ofactive ingredient, 1.8 mg methylparaben, 0.2 mg propylparaben and 10 mgmethylcellulose. The solution is dispensed into 1 mL vials.

Lung Inhaler

A homogeneous mixture of the active ingredient in polysorbate 80 isprepared such that the final concentration of the active ingredient willbe 10 mg per container and the final concentration of polysorbate 80 inthe container will be 1% by weight. The mixture is dispensed into eachcan, the valves are crimped onto the can and the required amount ofdichlorotetrafluoroethane is added under pressure.

The preferred crystalline form of Compound (I) may serve as component(a) of this invention and can independently be in any dosage form, suchas those described above, and can also be administered in variouscombinations, as described above. In the following description component(b) is to be understood to represent one or more agents as describedherein suitable for combination therapy.

Thus, the crystalline forms of Compound (I) may be used alone or incombination with other diagnostic, anticoagulant, antiplatelet,fibrinolytic, antithrombotic, and/or profibrinolytic agents. Forexample, adjunctive administration of Factor Xa inhibitors with standardheparin, low molecular weight heparin, direct thrombin inhibitors (i.e.hirudin), aspirin, fibrinogen receptor antagonists, streptokinase,urokinase and/or tissue plasminogen activator may result in improvedantithrombotic or thrombolytic efficacy or efficiency. The crystalsdescribed herein may be administered to treat thrombotic complicationsin a variety of animals, such as primates, including humans, sheep,horses, cattle, pigs, dogs, rats and mice. Inhibition of Factor Xa maybe useful not only in the anticoagulant therapy of individuals havingthrombotic conditions, but also when inhibition of blood coagulation maybe required, such as to prevent coagulation of stored whole blood and toprevent coagulation in other biological samples for testing or storage.Thus, any Factor Xa inhibitor, including the crystalline forms ofCompound (I) as described herein, can be added to or contacted with anymedium containing or suspected of containing Factor Xa and in which itmay be desired to inhibit blood coagulation.

The crystalline forms of Compound (I) may be used in combination withany antihypertensive agent or cholesterol or lipid regulating agent, orconcurrently in the treatment of restenosis, atherosclerosis or highblood pressure. Some examples of agents that may be useful incombination with a novel form of Compound (I) according to the presentinvention in the treatment of high blood pressure include, for example,compounds of the following classes: beta-blockers, ACE inhibitors,calcium channel antagonists and alpha-receptor antagonists. Someexamples of agents that may be useful in combination with a compoundaccording to the invention in the treatment of elevated cholesterollevels or disregulated lipid levels include compounds known to be HMGCoAreductase inhibitors, or compounds of the fibrate class.

Accordingly, components (a) and (b) of the present invention may beformulated together, in a single dosage unit (that is, combined togetherin one capsule, tablet, powder, or liquid, etc.) as a combinationproduct. When component (a) and (b) are not formulated together in asingle dosage unit, the component (a) may be administered at the sametime as component (b) or in any order; for example component (a) of thisinvention may be administered first, followed by administration ofcomponent (b), or they may be administered in the reverse order. Ifcomponent (b) contains more that one agent, these agents may beadministered together or in any order. When not administered at the sametime, preferably the administration of component (a) and (b) occurs lessthan about one hour apart. Preferably, the route of administration ofcomponent (a) and (b) is oral. Although it may be preferable thatcomponent (a) and component (b) both be administered by the same route(that is, for example, both orally) or dosage form, if desired, they mayeach be administered by different routes (that is, for example, onecomponent of the combination product may be administered orally, andanother component may be administered intravenously) or dosage forms.

Pharmaceutical kits which may be useful for the treatment of variousdisorders, and which comprise a therapeutically effective amount of apharmaceutical composition comprising a novel form of Compound (I) inone or more sterile containers, are also within the ambit of the presentinvention. The kits may further comprise conventional pharmaceutical kitcomponents which will be readily apparent to those skilled in the art,once armed with the present disclosure. Sterilization of the containermay be carried out using conventional sterilization methodology wellknown to those skilled in the art.

The present invention is further described in the following examples.All of the examples are actual examples. These examples are not to beconstrued as limiting the scope of the appended claims.

EXAMPLES Example 1 Preparation of Form N-3

50 g of dried crude Compound (I) was dissolved in 500 mL of CH₂Cl₂ atroom temperature. 150 mL 6N NH₄OH was charged to the solution andagitated for a minimum of 30 minutes at room temperature. Phasesepration occurred in about 15-30 minutes and two phases were separated.The organic phase was agitated with 150 mL of 1N HCl for at least 30minutes and separated from the aqueous phase. The organic phase wasagitated with 150 mL of deionized water for at least 30 minutes andseparated from the aqueous phase.

The organic solution was polish filtered through 1 micron filter. 1100mL of EtOAc was added to the filtered organic solution. Some precipitatemight form due to the low solubility of the product in EtOAc. Thesolution/slurry was distillated at <55° C. (acket tempeature) and180-400 Hg pressure. About 1000 mL of was CH₂Cl₂ removed. Another 500 mLof EtOAc was added. Distillation was continued until the final volume isabout 15-20 mL/g of input. The slurry was filtered by vacuum filtrationwith 12 cm ID Buchner funnel and Whatman® 4 filter paper. The resultingwet cake was deliquored thoroughly and washed with EtOAc (3×100 mL),then deliquored thoroughly again and washed with n-Heptane (2×100 mL).The wet cake was dried at 50-55° C. under vaccum 20-28″ Hg till a LOD of<1%.

Example 2

Polymorph Transformation from N-3 to N-1

Slurry 10 g of Example 1 in 150 mL of 200 proof Ethanol (15 mL/g) washeated up to 65° C. and held at 65° C. for 10 minutes. 0.5 g (5%) ofForm N-1 seeds was added and agitated at 250 rpm. The slurry was held at65° C. for 120-180 minutes until all crystals transformed to Form N-1(monitored by Raman). The slurry was cooled to 20° C. over 60 minutes.The slurry was filtered and washed with 2×30 mL of EtOH. The resultingwet cake was dried at 60° C. and >25″ Hg vacuum. The dry material wasde-lumped through 40 mesh screen to obtain From N-1 crystals.

Example 3 Preparation of Form H2-2

50 mg of dried crude Compound (I) was dissolved in 4 mL THF. 6 mL ofwater was added. The solution was vacumm concentrated at 300-500 mm. Hgfor 16-24 hours or until crystals appear. This procedure was duplicatedwith IPA instead of THF.

Example 4 Preparation of Form DC-4

500 mg of dried crude Compound (I) was dissolved in 6 mL of CH₂Cl₂. Thesolution was concentrated by opening the cap to let CH₂Cl₂ evaporatesuntil crystals appearred. The slurry was filtered and vacuum dried underroom temperature.

Example 5 Preparation of Form EGDA. 5-5

1.08 g of Example 1 was dissolved in 8.5 mL of CH₂Cl₂ at 40° C. 1 mL ofthis solution was charged to 36 mL of diacetoxy ethyleneglycol (EGDA).15 μL of EGDA. 5-5 seeds in EGDA was then charged to the crystallizationvessel. The remaining 7.5 mL of the CH₂Cl₂ solution was charged to thecrystallization vessel. A heavy slurry containing EGDA. 5-5 was formedwithin 20 minutes.

X-ray powder diffraction (PXRD) data were obtained using a Bruker C2GADDS (General Area Detector Diffraction System). The radiation was CuKα (40 KV, 50 mA). The sample-detector distance was 15 cm. Powdersamples were placed in sealed glass capillaries of 1 mm or less indiameter; the capillary was rotated data collection. Data were collectedfor 3≦2θ≦35° with a sample exposure time of at least 2000 seconds. Theresulting two-dimensional diffraction arcs were integrated to create atraditional 1-dimensional PXRD pattern with a step size of 0.02 degrees2θ in the range of 3 to 35 degrees 2θ.

Characteristic diffraction peak positions (degrees 2θ±0.1) at roomtemperature or at a specified temperature were determined based on ahigh quality pattern collected with a diffractometer (CuKα) with aspinning capillary with 2θ calibrated with a NIST or other suitablestandard.

Single crystal X-ray data were collected on a Bruker-Nonius CAD4 serialdiffractometer (Bruker Axs, Inc., Madison Wis.). Unit cell parameterswere obtained through least-squares analysis of the experimentaldiffractometer settings of 25 high-angle reflections. Intensities weremeasured using Cu Kα radiation (λ=1.5418 Å) at a constant temperaturewith the θ-2θ variable scan technique and were corrected only forLorentz-polarization factors. Background counts were collected at theextremes of the scan for half of the time of the scan. Alternately,single crystal data were collected on a Bruker-Nonius Kappa CCD 2000system using Cu Kα radiation (λ=1.5418 Å). Indexing and processing ofthe measured intensity data were carried out with the HKL2000 softwarepackage in the Collect program suite R. Hooft, Nonius B. V. (1998). Whenindicated, crystals were cooled in the cold stream of an Oxfordcryogenic system during data collection.

The structures were solved by direct methods and refined on the basis ofobserved reflections using either the SDP software package SDP,Structure Determination Package, Enraf-Nonius, Bohemia, N.Y.) with minorlocal modifications or the crystallographic package, MAXUS (maXussolution and refinement software suit: S. Mackay, C. J. Gilmore, C.Edwards, M. Tremayne, N. Stewart, and K. Shankland. maXus is a computerprogram for the solution and refinement of crystal structures fromdiffraction data.

The derived atomic parameters (coordinates and temperature factors) wererefined through full matrix least-squares. The function minimized in therefinements was Σ_(W)(|F_(O)|-|F_(C)|)². R is defined asΣ||F|-|F||/Σ|F_(O)| whileR_(W)=[Σ_(W)(|F_(O)|-|F_(C)|)²/Σ_(W)|F_(O)|²]^(1/2) where w is anappropriate weighting function based on errors in the observedintensities. Difference maps were examined at all stages of refinement.Hydrogen atoms were introduced in idealized positions with isotropictemperature factors, but no hydrogen parameters were varied.

“Hybrid” simulated powder X-ray patterns were generated as described inthe literature (Yin. S.; Scaringe, R. P.; DiMarco, J.; Galella, M. andGougoutas, J. Z., American Pharmaceutical Review, 2003, 6(2), 80). Theroom temperature cell parameters were obtained by performing a cellrefinement using the CellRefine.xls program. Input to the programincludes the 2-theta position of ca. 10 reflections, obtained from theexperimental room temperature powder pattern; the corresponding Millerindices, hkl, were assigned based on the single-crystal data collectedat low temperature. A new (hybrid) PXRD was calculated (by either of thesoftware programs, Alex or LatticeView) by inserting the molecularstructure determined at low temperature into the room temperature cellobtained in the first step of the procedure. The molecules are insertedin a manner that retains the size and shape of the molecule and theposition of the molecules with respect to the cell origin, but, allowsintermolecular distances to expand with the cell.

Differential scanning calorimetry (DSC) experiments were performed in aTA Instruments™ model Q1000. The sample (about 2-6 mg) was weighed in analuminum pan and recorded accurately recorded to a hundredth of amilligram, and transferred to the DSC. The instrument was purged withnitrogen gas at 50 mL/min. Data were collected between room temperatureand 300° C. at 10° C./min heating rate. The plot was made with theendothermic peaks pointing down.

Thermal gravimetric analysis (TGA) experiments were performed in a TAInstruments™ model Q500. The sample (about 10-30 mg) was placed in aplatinum pan previously tared. The weight of the sample was measuredaccurately and recorded to a thousand of a milligram by the instrumentThe furnace was purged with nitrogen gas at 100 mL/min. Data werecollected between room temperature and 300° C. at 10° C./min heatingrate.

Moisture sorption isotherms for N-1 were collected in a VTI SGA-100Symmetric Vapor Analyzer using about 10 mg sample. The sample was driedat 60° C. until the loss rate of 0.0005 wt %/min was obtained for 10minutes. The sample was tested at 25° C. and 4, 5, 15, 25, 35, 45, 50,65, 75, 85, and 95% RH. Equilibration at each RH was reached when therate of 0.0003 wt %/min for 35 minutes or a maximum of 600 minutes wasachieved.

Various crystalline forms of Compound (I) and its solvates were preparedand are tabulated in Table 1. The unit cell data and other propertiesfor these examples are tabulated in Tables 2a and 2b. The unit cellparameters were obtained from single crystal X-ray crystallographicanalysis. A detailed account of unit cells can be found in Chapter 3 ofStout & Jensen, “X-Ray Structure Determination: A Practical Guide”,(MacMillian, 1968).

TABLE 1 Form Description N-1 Neat crystal N-3 Neat crystal H2-2Dihydrate crystal DC-4 Dichloromethane solvate crystal

TABLE 2a Unit Cell Parameters Form T(° C.) a(Å) b(Å) c(Å) α° β° γ° N-1+22 9.534(1) 9.842(1) 13.469(1) 87.95(1) 83.18(1) 70.22(1) N-3 +228.959(3) 9.840(2) 14.826(6) 76.27(2) 86.38(2) 69.18(2) N-3 −50 8.933(1)9.811(3) 14.751(5) 76.32(2) 85.99(2) 69.01(2) H2-2* room 16.627 17.37019.005 71.65 78.55 88.04 temp. H2-2** −50 16.445(2)  17.319(1) 18.997(2) 71.65(1) 78.86(1) 87.78(1) DC-4 +22 8.951(2) 9.789(3)17.263(4) 69.30(2) 83.24(2) 69.78(2) DC-4 −50 8.933(1) 9.778(1)17.227(1) 69.19(1) 83.06(1) 69.66(1) *Generated from hybrid calculations**The cell for form H2-2 is either twinned or pseudo along a

TABLE 2b Unit Cell Parameters (continued) Solvent Sites for Form T(° C.)V_(m)(Å³) Z′ SG R Z′ N-1 +22 1180.8(2) 1 P-1 0.06 None N-3 +22   1186(1)1 P-1 0.15 None N-3 −50 1172.6(6) 1 P-1 0.07 None H2-2 room 5103.6 4 P-1N/A 2H₂O temp. H2-2 −50 5038.7(7) 4 P-1 0.07 2H₂O DC-4 +22 1327.7(5) 1P-1 0.6 1 CH₂CL₂ DC-4 −50 1318.9(2) 1 P-1 0.052 1 CH₂CL₂ Notes forTables: T is the temperature for the crystallographic data. Z′ is thenumber of molecules of Compound (I) in each asymmetric unit (not unitcell). V_(m) is the molar volume, V(unit cell)/(Z drug molecules percell). SG is the crystallographic space group. R is the R-factor(measure of the quality of the refinement).

The fractional atomic coordinates for the various crystalline forms aretabulated in Tables 3 to 7.

TABLE 3 Positional Parameters and Their Estimated Standard Deviationsfor Form N-1 at room temperature Atom x y z B (iso) O8 0.0394(2)0.2922(2) 0.3315(1) 3.3 O16 0.7335(2) 0.2489(2) 0.3565(2) 5.7 O26−0.3835(2) 0.0761(2) 0.6244(2) 5.1 O31 0.0364(2) 0.2648(2) −0.1195(1)4.8 N1 0.3244(2) 0.2942(2) 0.2101(1) 2.5 N2 0.4619(2) 0.3090(2)0.1867(1) 2.8 N25 −0.2931(2) 0.1728(2) 0.7419(1) 2.8 C3 0.5174(2)0.3065(2) 0.2739(2) 2.5 C4 0.4166(2) 0.2903(2) 0.3540(2) 2.4 C50.4159(2) 0.2863(3) 0.4646(2) 3.1 C6 0.3171(2) 0.2020(3) 0.5083(2) 3.2N7 0.1692(2) 0.2485(2) 0.4678(1) 2.6 C8 0.1563(2) 0.2739(2) 0.3685(2)2.4 C9 0.2951(2) 0.2820(2) 0.3113(2) 2.2 C10 0.2435(2) 0.2903(2)0.1287(2) 2.4 C11 0.1795(2) 0.1849(3) 0.1212(2) 2.8 C12 0.1104(2)0.1796(3) 0.0369(2) 3.2 C13 0.1062(2) 0.2785(3) −0.0389(2) 3.1 C140.1696(3) 0.3842(3) −0.0311(2) 3.2 C15 0.2384(3) 0.3894(3) 0.0525(2) 2.9C16 0.6664(2) 0.3274(3) 0.2743(2) 3.2 C17 0.6411(3) 0.4873(4) 0.2933(3)6.0 C18 0.7647(3) 0.2822(5) 0.1780(3) 6.9 C19 0.0472(2) 0.2276(3)0.5318(2) 2.6 C20 0.0681(3) 0.0973(3) 0.5803(2) 4.4 C21 −0.0450(3)0.0794(3) 0.6484(2) 4.5 C22 −0.1786(2) 0.1912(3) 0.6675(2) 2.6 C23−0.2013(3) 0.3192(3) 0.6181(2) 3.2 C24 −0.0881(3) 0.3388(3) 0.5502(2)3.1 C26 −0.3931(3) 0.1096(3) 0.7123(2) 3.2 C27 −0.4979(3) 0.0896(3)0.7914(2) 4.1 C28 −0.4996(3) 0.1295(3) 0.8867(2) 4.6 C29 −0.3995(3)0.1951(4) 0.9113(2) 4.8 C30 −0.2987(3) 0.2147(3) 0.8391(2) 4.1 C320.0601(3) 0.3420(4) −0.2074(2) 5.2 H161 0.845 0.255 0.357 5.5

TABLE 4 Positional Parameters and Their Estimated Standard Deviationsfor Form N-3 at +22° C. Atom x y z B(A2) O8 0.000(2) −0.106(2) −0.126(1)3.0 O16 0.356(2) 0.378(2) −0.201(1) 3.2 O26 0.576(2) −0.657(2) 0.245(1)3. O31 −0.301(3) −0.017(2) −0.494(2) 5.1 N1 0.049(2) 0.143(2) −0.270(2)1.9 N2 0.083(3) 0.276(2) −0.310(2) 2.1 N7 0.202(3) −0.104(2) −0.045(2)2.2 N25 0.369(3) −0.684(2) 0.181(2) 2.0 C3 0.162(3) 0.284(3) −0.237(2)1.9 C4 0.190(3) 0.171(3) −0.156(2) 1.8 C5 0.259(3) 0.136(3) −0.067(2)2.1 C6 0.329(3) −0.036(3) −0.031(2) 2.9 C8 0.106(3) −0.053(3) −0.118(2)2.4 C9 0.113(3) 0.082(3) −0.189(2) 1.3 C10 −0.045(3) 0.108(3) −0.335(2)2.8 C11 −0.175(4) 0.208(3) −0.375(2) 3.9 C12 −0.255(4) 0.170(3)−0.438(2) 3.5 C13 −0.198(4) 0.010(3) −0.436(2) 1.6 C14 −0.067(3)−0.090(3) −0.396(2) 2.3 C15 0.020(3) −0.053(3) −0.333(2) 1.7 C160.212(3) 0.434(3) −0.252(2) 1.4 C17 0.083(3) 0.538(3) −0.218(2) 2.9 C180.241(4) 0.476(3) −0.353(2) 3.7 C19 0.234(3) −0.252(3) 0.019(2) 2.3 C200.234(3) −0.270(3) 0.108(2) 3.3 C21 0.289(3) −0.421(3) 0.168(2) 2.8 C220.318(3) −0.534(3) 0.118(2) 3.1 C23 0.312(3) −0.514(3) 0.030(2) 2.5 C240.261(3) −0.367(3) −0.029(2) 2.8 C26 0.503(4) −0.743(3) 0.240(2) 2.9 C270.557(4) −0.901(3) 0.289(2) 3.7 C28 0.469(3) −0.983(3) 0.272(2) 2.6 C290.339(3) −0.925(3) 0.215(2) 2.7 C30 0.293(3) −0.783(3) 0.166(2) 2.0 C32−0.268(4) −0.179(4) −0.487(3) 2.0 H161 0.399 0.474 −0.211

TABLE 4a Positional Parameters and Their Estimated Standard Deviationsfor Form N-3 at −50° C. Atom x y z B(iso) O8 0.0016(5) −0.1082(5)−0.1272(4) 2.4 O16 0.3570(6) 0.3809(5) −0.2021(4) 3.4 O26 0.5809(6)−0.6620(5) 0.2465(4) 3.0 O31 −0.3017(6)   −0.0191(6) −0.4930(4) 3.7 N10.0511(7) 0.1465(6) −0.2708(4) 2.0 N2 0.0845(7) 0.2734(6) −0.3080(5) 2.1N7 0.2007(7) −0.1010(6) −0.0417(4) 2.0 N25 0.3750(7) −0.6924(6)0.1798(4) 1.9 C3 0.1673(8) 0.2892(7) −0.2413(6) 2.1 C4 0.1883(8)0.1731(7) −0.1599(5) 1.7 C5 0.2594(9) 0.1348(7) −0.0656(6) 2.2 C60.3241(9) −0.0359(8) −0.0326(6) 2.4 C8 0.0993(8) −0.0524(7) −0.1173(5)1.7 C9 0.1135(8) 0.0824(7) −0.1823(5) 1.9 C10 −0.0337(8)   0.0997(8)−0.3290(6) 2.1 C11 −0.1648(9)   0.2042(8) −0.3796(6) 2.5 C12−0.2529(9)   0.1627(8) −0.4347(6) 2.6 C13 −0.2037(9)   0.0128(8)−0.4402(5) 2.3 C14 −0.0674(9)   −0.0920(7) −0.3917(6) 2.2 C15 0.0191(8)−0.0500(7) −0.3369(6) 1.9 C16 0.2140(9) 0.4253(8) −0.2560(6) 2.7 C17 0.077(1) 0.5479(8) −0.2175(7) 3.4 C18  0.242(1) 0.4832(8) −0.3586(7)3.9 C19 0.2326(8) −0.2506(7) 0.0155(6) 2.0 C20 0.2442(9) −0.2752(7)0.1103(5) 1.9 C21 0.2874(9) −0.4195(8) 0.1664(6) 2.4 C22 0.3224(8)−0.5391(7) 0.1225(6) 2.1 C23 0.3079(9) −0.5142(7) 0.0277(6) 2.3 C240.2645(9) −0.3716(8) −0.0279(5) 2.5 C26 0.5029(8) −0.7401(7) 0.2397(6)2.1 C27 0.5528(8) −0.8988(8) 0.2894(6) 2.2 C28 0.4708(9) −0.9844(8)0.2761(6) 2.5 C29 0.3398(9) −0.9297(7) 0.2141(6) 2.3 C30 0.2905(8)−0.7802(8) 0.1670(6) 2.2 C32 −0.275(1) −0.1750(9) −0.4863(7) 4.4 H1610.3991 0.4735 −0.2109 8.0

TABLE 5 Positional Parameters for Form H2-2 at −50° C. Atom x y z B(iso)O8 0.1543 0.6836 0.3918 3 O8′ 0.5403 0.2894 0.0917 3 O16 0.2214 0.73390.0266 2 O16′ 0.4957 0.2637 0.4465 4 O26 0.0920 0.3990 0.6840 4 O26′0.6314 0.5725 −0.2065 4 O31 0.2574 1.0232 0.3799 3 O31′ 0.4679 −0.04370.0936 3 O48 0.6868 0.6943 0.3909 4 O56 0.7191 0.7369 0.0328 3 O660.6301 0.3948 0.6892 4 O71 0.7520 1.0357 0.3816 4 O78 0.0485 0.28690.0842 3 O86 0.0093 0.2516 0.4409 3 O90 0.5944 0.4050 0.8345 4 O920.6569 0.5655 0.6510 8 O93 0.6733 0.7114 0.5387 5 O94 0.1204 0.56700.6442 5 O95 0.1577 0.7128 0.5326 4 O96 0.1351 0.5683 −0.2135 5 O970.3824 0.7349 0.0475 3 O98 0.0877 0.4030 0.8295 4 O99 0.8785 0.73360.0560 3 O101 −0.0351 −0.0475 0.0896 3 N1 0.1932 0.8035 0.2365 2 N1′0.5175 0.1713 0.2468 2 N2 0.1930 0.8388 0.1614 2 N2′ 0.5046 0.14010.3244 3 N7 0.1545 0.5850 0.3362 2 N7′ 0.5830 0.3826 0.1399 2 N25 0.06800.3268 0.6079 2 N25′ 0.6675 0.6400 −0.1306 2 N41 0.6983 0.8137 0.2370 2N42 0.6931 0.8469 0.1630 2 N47 0.6657 0.5953 0.3409 2 N65 0.5759 0.33770.6140 2 N71 0.0225 0.1686 0.2391 2 N72 0.0149 0.1358 0.3150 3 N770.0843 0.3813 0.1340 2 N95 0.1694 0.6381 −0.1387 2 C3′ 0.5209 0.20260.3478 3 C3 0.1791 0.7781 0.1355 2 C4′ 0.5426 0.2730 0.2866 2 C4 0.17110.7034 0.1938 2 C5′ 0.5648 0.3588 0.2789 4 C5 0.1509 0.6185 0.1987 2 C6′0.6039 0.4004 0.2045 7 C6 0.1814 0.5607 0.2667 3 C8 0.1641 0.6637 0.33382 C8′ 0.5553 0.3068 0.1460 2 C9′ 0.5403 0.2509 0.2229 2 C9 0.1802 0.72120.2576 1 C10′ 0.5034 0.1187 0.2053 2 C10 0.2081 0.8567 0.2769 2 C11′0.4294 0.0754 0.2260 3 C11 0.2610 0.8351 0.3281 2 C12′ 0.4141 0.02060.1888 3 C12 0.2790 0.8880 0.3650 2 C13 0.2423 0.9637 0.3495 2 C13′0.4748 0.0089 0.1318 2 C14 0.1878 0.9860 0.2993 2 C14′ 0.5501 0.05370.1107 3 C15′ 0.5636 0.1077 0.1482 2 C15 0.1713 0.9317 0.2633 2 C16′0.5213 0.1905 0.4299 3 C16 0.1733 0.7943 0.0531 2 C17 0.0845 0.78190.0466 3 C17′ 0.6090 0.1794 0.4421 6 C18′ 0.4637 0.1196 0.4824 6 C180.2073 0.8784 0.0054 3 C19 0.1335 0.5213 0.4065 2 C19′ 0.6015 0.44500.0688 2 C20′ 0.6576 0.4328 0.0086 2 C20 0.1816 0.5042 0.4593 3 C210.1608 0.4391 0.5265 3 C21′ 0.6781 0.4966 −0.0581 2 C22 0.0920 0.39440.5398 2 C22′ 0.6422 0.5715 −0.0637 2 C23 0.0394 0.4106 0.4857 2 C23′0.5857 0.5835 −0.0036 2 C24′ 0.5648 0.5203 0.0618 2 C24 0.0614 0.47450.4182 2 C26 0.0685 0.3336 0.6790 2 C26′ 0.6585 0.6367 −0.2015 3 C27′0.6810 0.7089 −0.2635 3 C27 0.0404 0.2646 0.7423 3 C28′ 0.7107 0.7767−0.2539 4 C28 0.0135 0.1949 0.7352 3 C29′ 0.7189 0.7764 −0.1812 3 C290.0133 0.1910 0.6616 2 C30′ 0.6968 0.7099 −0.1220 3 C30 0.0409 0.25550.6007 2 C32 0.3233 1.0087 0.4230 5 C32′ 0.3884 −0.0839 0.1072 3 C430.6797 0.7840 0.1393 2 C44 0.6757 0.7108 0.1975 2 C45 0.6561 0.62470.2052 3 C46 0.6796 0.5693 0.2718 6 C48 0.6806 0.6736 0.3356 2 C490.6885 0.7317 0.2593 2 C50 0.7124 0.8676 0.2775 2 C51 0.6665 0.93810.2676 2 C52 0.6813 0.9931 0.3044 3 C53 0.7408 0.9763 0.3501 2 C540.7846 0.9067 0.3600 3 C55 0.7696 0.8509 0.3242 2 C56 0.6729 0.79820.0577 2 C57 0.7055 0.8820 0.0066 4 C58 0.5828 0.7849 0.0525 3 C590.6502 0.5317 0.4126 2 C60 0.6781 0.4561 0.4185 3 C61 0.6553 0.39120.4864 3 C62 0.6056 0.4056 0.5469 2 C63 0.5810 0.4830 0.5437 3 C640.6032 0.5477 0.4763 3 C66 0.5894 0.3378 0.6840 2 C67 0.5563 0.26870.7462 3 C68 0.5155 0.2061 0.7368 3 C69 0.5063 0.2099 0.6633 3 C700.5351 0.2750 0.6047 2 C72 0.8209 1.0270 0.4204 5 C73 0.0342 0.19650.3388 3 C74 0.0557 0.2675 0.2788 2 C75 0.0806 0.3509 0.2723 4 C760.0862 0.4038 0.2006 10 C78 0.0596 0.3052 0.1395 2 C79 0.0470 0.24850.2157 2 C80 0.0063 0.1166 0.1969 2 C81 0.0668 0.1024 0.1410 2 C820.0502 0.0477 0.1056 3 C83 −0.0263 0.0076 0.1257 2 C84 −0.0879 0.02260.1806 2 C85 −0.0706 0.0781 0.2167 3 C86 0.0390 0.1814 0.4216 4 C87−0.0132 0.1097 0.4735 10 C88 0.1310 0.1767 0.4298 8 C89 0.1031 0.44410.0624 2 C90 0.0681 0.5190 0.0554 2 C91 0.0886 0.5825 −0.0120 2 C920.1446 0.5694 −0.0707 2 C93 0.1788 0.4935 −0.0639 2 C94 0.1580 0.43070.0027 2 C96 0.1622 0.6326 −0.2091 3 C97 0.1872 0.7037 −0.2712 4 C980.2176 0.7726 −0.2631 4 C99 0.2233 0.7736 −0.1904 3 C100 0.2000 0.7065−0.1299 3 C102 −0.1144 −0.0885 0.1065 3 H16 0.2845 0.7358 0.0362 4 H860.0611 0.2817 0.4510 4 H56 0.7821 0.7373 0.0430 4 H86 0.06111 0.28170.4510 4 H16′ 0.4282 0.2688 0.4512 4

TABLE 6 Positional Parameters and Their Estimated Standard Deviationsfor Form DC-4 at +22° C. Atom x y z B(iso) CL1 0.2976(3) 0.2977(2)−0.6245(1) 7.68(7)  CL2 0.2083(3) 0.3384(2) −0.4662(1) 7.46(7)  O80.0120(4) −0.0938(4) −0.1141(2) 3.1(1) O16 0.3579(4) 0.4154(4)−0.1701(2) 3.7(1) O26 0.5755(4) −0.7135(4) 0.2190(2) 3.4(1) O31−0.1986(5) 0.0439(5) −0.4622(2) 5.1(1) N1 0.0616(5) 0.1901(4) −0.2380(3)2.4(1) N2 0.0936(5) 0.3272(4) −0.2694(3) 2.5(1) N7 0.2060(5) −0.1027(4)−0.0363(3) 2.1(1) N25 0.3661(5) −0.7314(4) 0.1626(3) 2.3(1) C1 0.1438(8)0.3265(7) −0.5530(4) 5.4(2) C3 0.1747(6) 0.3300(5) −0.2098(3) 2.2(1) C40.1938(6) 0.1967(5) −0.1399(3) 2.2(1) C5 0.2654(7) 0.1372(5) −0.0555(3)2.8(1) C6 0.3252(6) −0.0368(6) −0.0270(3) 2.7(1) C8 0.1073(6) −0.0376(5)−0.1030(3) 2.1(1) C9 0.1220(6) 0.1091(5) −0.1602(3) 2.1(1) C10−0.0112(6) 0.1507(5) −0.2923(3) 2.2(1) C11 0.0532(6) 0.0089(6)−0.3036(3) 2.7(1) C12 −0.0151(7) −0.0226(6) −0.3596(3) 2.9(1) C13−0.1416(7) 0.0857(6) −0.4067(3) 3.3(2) C14 −0.2105(7) 0.2307(6)−0.3961(4) 3.2(2) C15 −0.1414(7) 0.2594(6) −0.3374(3) 3.0(2) C160.2234(7) 0.4685(6) −0.2221(3) 2.8(1) C17 0.0866(7) 0.5851(6) −0.1947(4)4.0(2) C18 0.2662(8) 0.5381(6) −0.3122(4) 4.3(2) C19 0.2333(6)−0.2608(6) 0.0144(3) 2.2(1) C20 0.2686(7) −0.3763(6) −0.0221(3) 3.1(2)C21 0.3105(7) −0.5294(5) 0.0278(3) 2.8(1) C22 0.3206(6) −0.5701(5)0.1120(3) 2.2(1) C23 0.2826(6) −0.4576(6) 0.1497(3) 2.5(1) C24 0.2391(7)−0.3036(6) 0.0994(3) 2.7(1) C26 0.4965(6) −0.7920(6) 0.2141(3) 2.6(1)C27 0.5380(7) −0.9558(6) 0.2616(4) 3.2(2) C28 0.4540(7) −1.0418(6)0.2517(4) 3.3(2) C29 0.3206(7) −0.9716(6) 0.1978(4) 3.4(2) C30 0.2813(6)−0.8186(5) 0.1541(3) 2.6(1) C32 −0.3472(8) 0.1345(8) −0.5008(4) 5.5(2)H161 0.401 0.513 −0.180 4.3*

TABLE 6a Positional Parameters and Their Estimated Standard Deviationsfor Form DC-4 at −50° C. Atom x y z B(iso) CL1 0.3018(1) 0.2953(1)−0.6245(1) 6.7 CL2 0.2079(1) 0.3403(1) −0.4660(1) 6.5 O8 0.0094(2)−0.0930(2) −0.1142(1) 3.5 O16 0.3574(2) 0.4191(2) −0.1706(1) 4.0 O260.5772(2) −0.7162(2) 0.2196(1) 3.8 O31 −0.1973(3) 0.0409(3) −0.4625(1)5.0 N1 0.0605(2) 0.1929(2) −0.2389(1) 2.9 N2 0.0934(2) 0.3289(2)−0.2701(1) 3.1 N7 0.2057(2) −0.1025(2) −0.0362(1) 3.0 N25 0.3675(2)−0.7338(2) 0.1626(1) 2.9 C3 0.1726(3) 0.3318(3) −0.2102(2) 2.9 C40.1925(3) 0.1979(3) −0.1400(2) 2.8 C5 0.2627(3) 0.1397(3) −0.0553(2) 3.3C6 0.3270(3) −0.0362(2) −0.0278(2) 3.4 C8 0.1056(3) −0.0366(3)−0.1039(2) 2.9 C9 0.1209(3) 0.1114(3) −0.1605(2) 2.7 C10 −0.0125(3)0.1525(3) −0.2937(1) 3.0 C11 0.0541(3) 0.0089(3) −0.3037(1) 3.1 C12−0.0122(3) −0.0235(3) −0.3606(2) 3.6 C13 −0.1446(3) 0.0870(3) −0.4078(2)3.5 C14 −0.2112(3) 0.2289(3) −0.3969(2) 3.7 C15 −0.1453(3) 0.2623(3)−0.3393(2) 3.4 C16 0.2204(3) 0.4722(3) −0.2232(2) 3.2 C17 0.0826(3)0.5907(3) −0.1955(2) 4.1 C18 0.2666(3) 0.5409(3) −0.3129(2) 4.2 C190.2337(4) −0.2621(3) 0.0143(2) 2.9 C20 0.2411(3) −0.3045(3) 0.1003(2)3.1 C21 0.2834(3) −0.4589(3) 0.1493(2) 3.1 C22 0.3201(3) −0.5720(3)0.1123(2) 3.0 C23 0.3103(3) −0.5302(3) 0.0269(2) 3.3 C24 0.2671(3)−0.3747(3) −0.0222(2) 3.4 C26 0.4994(3) −0.7969(3) 0.2159(2) 3.0 C270.5377(3) −0.9595(3) 0.2620(2) 3.5 C28 0.4547(3) −1.0457(3) 0.2524(2)3.8 C29 0.3237(3) −0.9756(3) 0.1971(2) 3.6 C30 0.2824(3) −0.8222(3)0.1545(2) 3.2 C32 −0.3499(4) 0.1329(4) −0.5009(2) 5.3 C99 0.1445(4)0.3247(4) −0.5539(2) 5.3

TABLE 7 Positional Parameters and Their Estimated Standard Deviationsfor Form EGDA.5-5 at +22° C. Atom x y z B(iso) O1 0.4623(4) 0.1510(4)0.6148(2) 4.2 O2 0.0977(4) −0.3162(4)   0.6680(2) 5.2 O3 −0.0246(4)  0.5987(4) 0.2811(2) 5.0 O4 0.6291(5) 0.1685(4) 0.9606(2) 6.0 N10.3770(4) −0.0590(4)   0.7381(2) 3.5 N2 0.3342(5) −0.1749(4)   0.7689(2)3.6 N3 0.2863(4) 0.1234(4) 0.5344(2) 3.7 N4 0.1711(4) 0.6450(4)0.3367(2) 3.6 C1 0.2710(5) −0.2106(5)   0.7094(3) 3.4 C2 0.2703(5)−0.1159(5)   0.6388(3) 3.4 C3I 0.2226(6) −0.1031(6)   0.5530(3) 4.0 C4I0.1683(6) 0.0553(5) 0.5254(3) 4.2 C5 0.3681(5) 0.0941(5) 0.6039(3) 3.2C6 0.3388(5) −0.0231(5)   0.6589(3) 3.3 C7 0.4479(5) 0.0004(5) 0.7917(3)3.2 C8I 0.5696(6) −0.0927(5)   0.8344(3) 3.8 C9I 0.6348(6) −0.0418(6)  0.8910(3) 4.4 C10 0.5762(6) 0.1051(6) 0.9060(3) 3.9 C11I 0.4520(6)0.2004(6) 0.8624(3) 4.1 C12I 0.3883(6) 0.1490(5) 0.8059(3) 3.8 C130.2191(6) −0.3402(5)   0.7211(3) 4.2 C14I 0.3621(7) −0.4753(6)  0.6941(4) 5.3 C15I 0.1528(8) −0.3581(7)   0.8105(4) 6.3 C16 0.2728(5)0.2516(5) 0.4842(3) 3.4 C17I 0.2501(5) 0.3987(3) 0.0482(13) 3.6 C18I0.2546(5) 0.3777(5) 0.3509(3) 3.6 C19 0.2094(5) 0.5101(5) 0.3875(3) 3.4C20I 0.1981(6) 0.5145(5) 0.4718(3) 4.1 C21I 0.2291(6) 0.3875(6)0.5205(3) 4.1 C22 0.0517(5) 0.6775(6) 0.2843(3) 3.8 C23I 0.0231(6)0.8141(6) 0.2381(3) 4.4 C24I 0.1034(6) 0.9015(6) 0.2472(3) 4.5 C25I0.2206(6) 0.8635(6) 0.3010(3) 4.5 C26I 0.2528(6) 0.7352(6) 0.3445(3) 4.0C27I 0.7562(8) 0.0760(8) 1.0068(4) 6.6 O9  0.3580(19)  0.5331(15)0.9804(9) 9. C55  0.385(3)  0.490(2) 1.1175(15) 9.2 C56  0.427(3) 0.491(2) 1.0457(18) 7.6 O10  0.553(2)  0.4884(18) 1.0170(11) 10.9 C57 0.708(4)  0.479(3) 0.9269(19) 11.3 C58  0.849(4)  0.447(3) 0.9332(19)12.6 O11  0.855(2)  0.566(2) 0.9681(11) 10.5 O12  1.076(3)  0.395(3)1.0061(16) 14.4 C59  1.036(2)  0.506(3) 1.0115(13) 6.5 C60  1.004(3) 0.646(2) 1.0447(14) 8.4

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.

1. A pharmaceutical composition comprising a therapeutically effectiveamount of crystalline Form N-1 of3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-oneand a pharmaceutically acceptable carrier.
 2. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of crystalline Form N-1 of3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.
 3. A method according to claim 2, wherein thethromboembolic disorder is selected from the group consisting ofarterial cardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, and thromboembolic disorders in the chambersof the heart.
 4. A method according to claim 2, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, first myocardial infarction,recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from (a) prosthetic valves or other implants, (b)indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e)hemodialysis, or (f) other procedures in which blood is exposed to anartificial surface that promotes thrombosis.